The impact of cancer on our society cannot be understated. In addition, to compound matters, the incidence of some cancers is increasing. For example, the incidence of melanoma as a cancer type is rising at a rate second only to lung cancer in women (see Rigel et al., J. Am. Acad. Derm. 35:1012, 1996). This crisis is compounded by the facts that, in contrast to most solid tumor types, melanoma affects a much younger population, metastasizes early in the course of disease, and fails to respond to current therapeutic regimens (see Herlyn, Molecular and Cellular Biology for Melanoma, Austin, R. G. Landes, 1993).
Despite the long history of clinical and research efforts directed towards understanding cancer, surprisingly little is known about the genetic lesions responsible for its genesis, progression, and clinical behavior. For example, in the case of melanoma, although many genes have been implicated in the genesis of this disease, only the INK4a and RAS genes have been shown to be true etiologic lesions in a formal genetic sense (Chin et al., Genes Devel. 11:2822, 1997). Moreover, advanced malignancy, which is among the most daunting conditions a clinician can face, represents the phenotypic endpoint of many successive genetic lesions that affect many oncogene and tumor suppressor gene pathways. Lesions that lead to such a condition, therefore, may differ from those required to maintain it. These mutations will represent rational therapeutic targets in the treatment of cancer.